Summary: The protein family of neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) together with their receptors (trkA, trkB, trkC) represents the best known group of neurotrophic factors and receptors. The neurotrophins act on various populations of central neurons which undergo degeneration in Alzheimer's disease (AD). NGF has been proposed as experimental treatment for AD based on its robust trophic influence on cholinergic neurons of the basal forebrain and the cholinergic neuron atrophy in AD. However, given the selectivity for NGF for cholinergic neurons, other neurotrophic factors will be necessary to protect all populations vulnerable in AD. The program project grant aims at identifying such molecules. The studies of specific aim #1 and #2 of this project will generate new neurotrophic factors and neurotrophins with different spectra of receptor selectivities. Mutants of neurotrophins and modified neurotrophins are produced and tested for activities in receptor binding and functional receptor assays. These molecules will be tested in studies of Projects 2 and 3 for biological activity in vitro and in vivo, in animal models mimicking the atrophy of specific neuronal populations vulnerable in AD. The studies proposed in specific aims #1 and #2 pursue the scientific goal to understand at a detailed molecular level the interaction between neurotrophins and their receptors. In particular, proposed studies with neurotrophic heterodimers will test the currently widely held believe that a single neurotrophin homodimer interacts with two trk-type receptor molecules.